The role of pathogen-experienced macrophage subsets in mediating lung immunity and heterologous protection

经历病原体的巨噬细胞亚群在介导肺免疫和异源保护中的作用

• 批准号: 10753773
• 负责人: William Clark Gause
• 金额: $ 77.95万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-14 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753773
• 关键词: 2019-nCoV; Address; Affect; Alveolar Macrophages; Antifungal Agents; Antigens; Basic Science; Biology; COVID-19; COVID-19 pandemic; Cells; Cessation of life; Communicable Diseases; Data; Defect; Embryo; Epigenetic Process; Event; Experimental Models; Exposure to; Gene Targeting; Goals; Health; Helminths; IFNAR1 gene; Immune; Immune response; Immunity; Impairment; In Vitro; Individual; Infection; Inflammation; Interferons; Knowledge; Literature; Lower Respiratory Tract Infection; Lung; Lung infections; Macrophage; Maintenance; Maps; Mediating; Mediator; Memory; Modification; Molecular; Morbidity - disease rate; Mus; Mycoses; Natural Immunity; Nature; Ontology; Outcome; Parasites; Pathway interactions; Play; Population; Primary Infection; Publishing; Recording of previous events; Role; STAT1 gene; Shapes; Signal Transduction; Specificity; Standardization; Stimulus; Testing; Therapeutic; Tissue Preservation; Tissues; Training; Viral; Virus; Virus Diseases; antimicrobial; blastomere structure; chronic infection; embryo cell; experience; extracellular; fungus; gain of function; helminth infection; human disease; in vivo; innate immune function; insight; instructor; loss of function; lung pathogen; monocyte; mortality; mouse model; neutrophil; novel; pathogen; pathogenic fungus; pathogenic virus; programs; pulmonary function; recruit; response; tissue injury; transcriptome

ABSTRACT: Infections of the lung significantly impact health worldwide, with non-tuberculosis lower respiratory infections causing 2.7 million deaths annually and chronic infections significantly contributing to impaired lung function and morbidity. Pulmonary macrophages are critical, front-line mediators of host protection against helminth parasites, fungi, and viruses. Despite the well-defined role of lung macrophages as crucial initiators of immunity to diverse sets of pathogens, our understanding of the cellular and molecular events that regulate macrophage responses in the lung remain poorly defined. For example, the precise mechanisms that allow pulmonary macrophages to eliminate both intracellular and extracellular pathogens while simultaneously mitigating tissue injury and preserving lung function remain elusive. Further, an emerging body of literature has now revealed that macrophage populations in the lung are more heterogeneous than originally appreciated. Specifically, it is now understood that alveolar macrophages present in the lung can originate from embryonic precursors (tissue- derived alveolar macrophages-TD-AMs) or from blood monocytes (monocyte-derived alveolar macrophages- Mo-AMs). Despite this important advance, it is currently unclear whether these ontologically distinct pulmonary macrophage populations perform comparable or distinct functions in mediating protection (reduction in pathogen burdens and/or maintenance of tissue integrity). Also, whether these distinct macrophage populations initiate similar or unique effector functions in the context of helminth, fungal, or viral challenges remains unknown. Finally, our understanding of how a previous exposure to one pulmonary pathogen alters the responsiveness of lung macrophages to a subsequent challenge with a distinct pathogen is poorly understood. This important gap in knowledge has become extremely evident during the COVID-19 pandemic where individual outcomes vary dramatically and we have a poor understanding of how one’s infectious past may contribute to these differences. The leaders of this project will employ their combined expertise to address these critical questions. The central hypothesis of this application is that infection with diverse pathogens program TD-AMs and Mo-AMs to perform distinct functions against heterologous pathogens while mitigating tissue injury. We further hypothesize that the pathogen-induced response of TD-AMs and Mo-AMs is critically shaped by neutrophil-derived signals and type I and III interferons. In three distinct and complementary aims we will use a combination of discovery-based studies combined with targeted in vitro and in vivo approaches to define the overlapping and unique contributions of tissue-derived macrophages and recruited monocyte-derived cells to host protective responses following helminth, fungal or viral infections. This thorough and comprehensive approach will allow us to gain an unprecedented understanding of fundamental innate immune functions. This novel insight may inform therapeutic strategies to target lung macrophage populations in a manner that will allow for the fine tuning of inflammation and pulmonary infection outcomes.

摘要： 肺部感染严重影响全世界的健康，非结核性下呼吸道感染 每年造成270万人死亡，慢性感染严重损害肺功能， 发病率肺巨噬细胞是保护宿主免受蠕虫寄生虫侵害的重要前线介质， 真菌和病毒。尽管肺巨噬细胞作为对多种疾病免疫的关键启动者的作用是明确的， 我们对调节巨噬细胞反应的细胞和分子事件的理解 肺内的肿瘤仍不明确。例如，允许肺巨噬细胞 消除细胞内和细胞外病原体，同时减轻组织损伤， 保持肺功能仍然很难。此外，一个新兴的文学机构现在已经揭示， 肺中的巨噬细胞群体比最初认识到的更加异质。具体来说，就是现在 应该理解，存在于肺中的肺泡巨噬细胞可以起源于胚胎前体（组织， 衍生的肺泡巨噬细胞-TD-AM）或来自血液单核细胞（单核细胞衍生的肺泡巨噬细胞- Mo-AM）。尽管取得了这一重要进展，但目前尚不清楚这些在本体上不同的肺 巨噬细胞群体在介导保护（减少病原体）方面执行相当或不同的功能 负担和/或维持组织完整性）。此外，这些不同的巨噬细胞群体是否启动了 在蠕虫、真菌或病毒攻击的情况下类似或独特的效应子功能仍然未知。 最后，我们对先前暴露于一种肺部病原体如何改变肺组织对 肺巨噬细胞对随后不同病原体攻击的反应知之甚少。这一重要差距 在COVID-19大流行期间，个人结果各不相同， 我们对一个人的传染性过去如何导致这些差异的理解很差。 该项目的领导者将利用他们的综合专业知识来解决这些关键问题。中央 该应用假设是，不同病原体的感染编程TD-AM和Mo-AM执行 在减轻组织损伤的同时对异源病原体具有独特的功能。我们进一步假设， TD-AM和Mo-AM的病原体诱导的应答由嗜热菌来源的信号和类型决定。 I和III干扰素。在三个不同而互补的目标中，我们将结合使用基于发现的 结合靶向体外和体内方法的研究，以确定重叠和独特的贡献 组织来源的巨噬细胞和募集的单核细胞来源的细胞对宿主的保护性反应， 蠕虫、真菌或病毒感染。这种彻底和全面的方法将使我们能够获得一个 对基本先天免疫功能的前所未有的理解。这种新的见解可能会告诉我们， 以允许微调的方式靶向肺巨噬细胞群体的治疗策略 炎症和肺部感染结果。